The thick myosin filaments are tethered to the Z lines by The force of contraction is transmitted both longitua cytoskeletal protein called titin. Titin is a very large, elastic dinally to the tendon (via myotendinous junctions) and protein (molecular weight, >3000 kDa) that extends from laterally to connective tissue adjacent to the muscle fibers the Z line to the center of the sarcomere and appears to be (via costameres). The myotendinous junction represents a important for organization and alignment of the thick fila-specialized region where the muscle fiber connects to the ments in the sarcomere. Some forms of muscular dystrophy tendon (
Fig. 12.4A and B).
Folding of the sarcolemma have been attributed to defects in titin (i.e., titinopathies). at the myotendinous junction results in an interdigitation
The cytoskeleton (including the intermediate filament of the tendon with the end of the muscle fiber, which protein desmin) participates in the highly organized align-increases the contact area between the muscle fiber and ment of sarcomeres. Desmin extends from the Z lines of the connective tissue and hence reduces the force per adjacent sarcomeres to the integrin protein complexes on unit area at the end of the muscle fiber. Some forms of the sarcolemma and thus participates in both the alignment muscular dystrophy are associated with decreased folding at the myotendinous junction. Proteins involved in longitudinal transmission of force at the myotendinous junction include the talin-vinculin-integrin protein complexes and the dystrophin-glycoprotein complexes. The myotendinous junction also contains Z disk proteins that have been implicated in signaling.
Lateral transmission of the force of contraction involves costameres, which link the Z lines of subsarcolemmal sarcomeres to extracellular matrix through a series of proteins (see
Fig. 12.4C ). This is particularly important for muscle fibers that do not extend the entire length of the muscle. The lateral transmission of force is also thought to stabilize the sarcolemma and to protect it from damage during contraction. The myotendinous junction and the costameres also contain signaling molecules.
Themusculardystrophiesconstituteagroupofgeneticallydetermineddegenerativedisorders.Duchenne’s muscular dystrophy (describedbyG.B.Duchennein1861)isthemostcommonofthemusculardystrophiesandaffects1per3500boys(3to5yearsofage).Severemusclewastingoccurs,andmostaffectedpatientsarewheelchairboundbytheageof12;manydieofrespiratoryfailureinadulthood(30to40yearsofage).Duchenne’smusculardystrophyisanX-linkedrecessivediseasethathasbeenlinkedtoadefectinthedystrophingenethatleadstoadeficiencyofthedystrophinproteininskeletalmuscle,brain,retina,andsmoothmuscle.Dystrophin isalarge(427-kDa)proteinthatispresentinlowabundance(0.025%)inskeletalmuscle.Itislocalizedontheintracellularsurfaceofthesarcolemmainassociationwithseveralintegralmembraneglycoproteins(formingadystrophin-glycoproteincomplex;
Fig.12.5 ).Thisdystrophin-glycoproteincomplexprovidesastructurallinkbetweenthesubsarcolemmalcytoskeletonofthemusclecellandtheextracellularmatrixandappearstostabilizethesarcolemmaandhencepreventcontraction-inducedinjury(rupture).Thedystrophin-glycoproteincomplexmayalsoserveasascaffoldforcellsignalingcascades.Theenzymenitricoxidesynthaseispresentinthedystrophin-glycoproteincomplex.